Dual microliter dosage system

ABSTRACT

The invention is a dual microliter dosage system. This system includes; a dual microliter dose ( 12 ) suspended below an outlet ( 5 ). The first dose is one ball of liquid ( 6 ) or medicament. The second dose is one ball of gas ( 7 ). A typical first dose can be 3, 4, 5, 6, 7, 8 or 9 microliters, including others. The second dose is approximately 2 microliters, including others.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] not applicable

STATEMENT OF FEDERALLY SPONSORED RESEARCH/DEVELOPMENT

[0002] not applicable

REFERENCE TO A MICROFICHE APPENDIX

[0003] not applicable

BACKGROUND OF THE INVENTION

[0004] There are many devices, designed to dispense microliter dosagesof liquid or medicament. For example, in Laibovitz, et al., U.S. Pat.No. 5,997,518, an apparatus and method for delivery of small volumes ofliquid is disclosed. This device utilizes a jet pump to dispense adosage having the form of many droplets. In column 14, Table 1,experimental results of Laibovitz include:

[0005] experiment No. 1: Average 2.0 microliter, Standard Deviation 0.5,Max 2.9 microliter, Min 1.3 microliter.

[0006] experiment No. 2: Average 6.0 microliter, Standard Deviation 0.6,Max 7.1 microliter, Min 4.7 microliter.

[0007] In Cohen, et al, U.S. Pat. No. 5,881,956, a microdispensingophthalmic pump is disclosed. This device dispenses a dose ofapproximately 5 microliters. The accuracy of the dosage for this deviceis unknown.

[0008] In Coffelt, Jr, U.S. Pat. No. 6,206,297, there is shown, devicesand methods of manufacturing a gasdrop. These devices are typically adual chamber device. The accuracy of the devices, for microliterdosages, is unknown.

[0009] Therefor the present invention will be greatly appreciated fordelivering a microliter dose of a liquid or medicament, or a dual dose.And further, the liquid dose is accurate to within plus or minus 0.5microliters.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

[0010] The invention is further described by reference to the appendeddrawings taken in conjunction with the following description where:

[0011]FIG. 1 is a perspective sectional view of a dual microliter dosagesystem (1); motive air via inlet (4) is ejecting the dual microliterdose (12).

[0012]FIG. 2 is a front view of a dispenser which includes: dosagesystem (1); tube (8); bottle (10).

[0013]FIG. 3 is a front perspective sectional view of a dual microliterdose (12) (microdose).

[0014]FIG. 4 is a sectional view of the system after beginning injectionof air; the liquid having a concave surface at the upstream end of theliquid.

[0015]FIG. 5 is a front sectional view of the system after beginninginjection of air; the concave surface of FIG. 2 beginning to form abubble (14); air injected into bubble (14) at point “B”.

[0016]FIG. 6 is a front sectional view of the system after beginninginjection of air; the opening at point “B” (FIG. 3) is closed; a bubble(14); a bubble (7); a dual microliter dose (15)(microdose) suspendedbelow the outlet (5).

[0017]FIG. 7 is a front perspective sectional view of the dualmicroliter dosage system (1) (static state).

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention resides in a dual microliter dosage system.This system is utilized to dispense a dual microliter dose (microdose).The microdose is a spheroidal ball of liquid (first dose) enclosing aspheroidal ball of gas (second dose).

[0019] The microdose may be the first dose enclosing a plurality of thesecond dose.

[0020] In Coffelt, Jr., U.S. patent application Ser. No. 09/706,329,filed Nov. 4, 2000 (abandoned), an apparatus and method formanufacturing a gasdrop is disclosed. The accuracy of the devices inthis Application, in the microliter range, is unknown.

[0021] The present invention includes a novel dual microliter dosagesystem. This system includes:

[0022] a flow channel having an inlet, and an outlet;

[0023] a first dose of a liquid disposed within the flow channel;

[0024] a second dose of a gas disposed within the liquid.

[0025] Embodiments of the present invention are hereinafter describedwith reference to the drawings, in which identical or correspondingparts are indicated by the same reference characters or numbers throughthe several views.

[0026] Referring to FIG. 7, there is shown, a left side perspectivesectional view of a dual microliter dosage system (1). The system issymmetrical, therefore, the right side view is a mirror image of FIG. 7.The system includes a conical tubular wall (2). The longitudinal axis ofwall (2) is vertical. The upper end of wall (2) is integrally formedwith a horizontal disk shaped wall (3). Wall (2) and wall (3) form aflow channel (33). Wall (3) is formed with a centrally located 0.25millimeter diameter opening (4).

[0027] The inner diameter of the upstream end of the flow channel(located at wall (3)) is 0.6 millimeters. The downstream end (5) of theflow channel is an annular arcuate surface, and the lowest extremity ofthis surface is a circle lying in a horizontal plane. The inner diameterof the flow channel (at 1 millimeter above said circle) is 1.4millimeters. The volume of the flow channel is calculated to beapproximately 8.9 microliters. For example, wall (2), wall (3), andopening (4) can be a standard dispensing tip from a 30 milliliter bottleof CLEAR EYES eye drops. The flow channel may have alternateconfigurations. For example, the flow channel may be cylindrical, 1millimeter ID and 2 millimeter OD, including others.

[0028] A microliter dose (6) is disposed within the flow channel asshown in FIG. 7. The lower surface of dose (6) is indicated by thearcuate line at point “A”. The upper surface of dose (6) is adjacent towall (3). Dose (6) can be TIMOLOL 0.5%, TIMOLOL 0.3%, CLEAR EYES,VISINE, or water, including others. TIMOLOL is a product manufactured byBausch & Lomb Pharmaceuticals, Inc. Tampa, Fla. 33637. CLEAR EYES is aproduct manufactured by Abbot Laboratories, Columbus, Ohio 43215. VISINEis a product manufactured by Pfizer Inc. New York, N.Y. 10017. Dose (6)is inherently in a static state (no motion). Dose (6) shown in FIG. 7 is5 microliters.

[0029] A ball of gas (bubble) (7) is centrally located in dose (6).Bubble (7) contains 2 microliters of a gas. The thickness of the liquidwall (between the bubble and wall (2) is inherently predetermined.Alternate volumes and quantities of bubble (7) can be empiricallydetermined. Dose (6) and bubble (7), in FIG. 7, is inherently in astatic state. A method of manufacturing system (1) (FIG. 7) includes:

[0030] (1.) With the longitudinal axis of the flow channel horizontal:inserting a syringe through the outlet; locating the tip of the needlenear wall (3); injecting dose (6). At this step, dose (6) is a unitaryball of liquid; the upper surface of the liquid is at wall (3).

[0031] (2.) Inserting a syringe though the outlet; locating the tip ofthe needle near the center of dose (6); injecting a gas into dose (6)via the needle. This step injects bubble (7) into dose (6).

[0032] Obviously there are variations of the above method. For example:wall (2) may be adapted with an inlet near wall (3), and an inlet nearthe center of the flow channel.

[0033] The flow channel can be any material which holds dose (6) in astatic state. For example, low density polyethylene, teflon, or vinyl.If plastic, the flow channel can be manufactured standard methods,including injection molding.

[0034] Referring to the above described dosage system (1), the followingis a method, among others, of use.

[0035] The system is fitted to a transparent vinyl tube (8). Tube (8) is6.3 millimeters OD, and 4.3 millimeters ID, and 15 millimeters length.Wall (3) is located at the end of tube (8). Tube (8) is co-axial withwall (2). An annular leak tight seal (9) rigidly attaches the system totube (8). For example, seal (9) and subsequent seals can be an epoxyresin.

[0036] The upper end of tube (8) is fitted with a 30 milliliter flexibleplastic bottle (10). A 1 millimeter diameter opening (16) is boredthrough the bottle wall at point “S”. The objective of opening (16) isto remove a possible undesired pressure drop across opening (4) duringinjection of dose (6) and bubble (7). For example, bottle (10) can be astandard 30 milliliter CLEAR EYES bottle. An annular leak tight seal(11) rigidly attaches the bottle to tube (8). The longitudinal axis ofthe bottle is co-axial with tube (8).

[0037] Dose (6) and bubble (7) are injected into the flow channel, asdescribed above, and shown in FIG. 7.

[0038] The bottle is held by a thumb at point “S” and a finger at point“T”. Points “S” and “T” are opposing points on the body of the bottle.These points are the typical points used to dispense a normal (approx 29microliter) pendant drop of liquid from the unaltered CLEAR EYES bottle.The thumb and finger apply opposing compressive force on the bottle.This compressive force closes opening (16). Alternate methods may beutilized to close opening (16) during compression of the bottle. For allof the above listed liquids (e.g. TIMOLOL), the total displacement ofthe bottle walls, required to dispense the microdose, is approximately 3millimeters. The total time required for this displacement isapproximately 550 milliseconds. Alternate displacements and collapsingvelocities can be empirically determined. The above volume reduction ofthe bottle creates a pressure drop across opening (4). Therefore, thegas disposed in the bottle is injected into the flow channel via opening(4) in the direction shown by the vertical arrow in FIG. 1. This gasflow (motive air) ejects the microdose (12) from the flow channelthrough the outlet, as shown in FIG. 1. While holding the dispenserabove a target, the microdose will fall vertically upon the target.

[0039] The configuration of the microdose, after ejection is inherentlypredetermined. This configuration is observed to be identical for eachtrial. For dose (6) between approximately 7 microliters to approximately9 microliters, the configuration of the microdose may be as shown inFIGS. 4, 5 and 6. For example: an 8 microliter dose (6) may have theconfiguration as shown in FIG. 6.

[0040] Given the above parameters, there are 2 possible configurationsas follows:

[0041] (1.) the microdose is one ball of liquid enclosing one ball ofair (microdose (12)).

[0042] (2.) the microdose is one ball of liquid enclosing at least 2compartments; and each compartment encloses a gas (microdose (15)).

[0043]FIG. 1, and FIG. 3 shows the configuration of a 3 microliter dose(6). This configuration is a spheroidal ball of liquid (6) enclosing aball of gas (7) (microdose (12)

[0044]FIG. 4, FIG. 5, and FIG. 6 show a possible sequence of eventswhich dispense the microdose in the form of a microdose (15). In FIG. 4,the upper surface of the dosage becomes concave. In FIG. 5, the concavesurface of the liquid begins to form a bubble, having an opening atpoint “B”. In FIG. 6, the opening at point “B” closes, forming a bubble(14). Therefore, the combination of dose (6), bubble (14), and bubble(7) forms a microdose (15).

[0045] The following experiments A to D, were executed utilizing theabove described method and dispenser. The equipment utilized in theseexperiments is as follows:

[0046] (1.) Prototype “P1”. This prototype has the form of the dispenseras shown and described above in FIG. 2. The flow channel (33), andopening (4) is provided by a standard dispensing tip from CLEAR EYES eyedrop bottle. The bottle (10) is a standard flexible plastic 30milliliter CLEAR EYES eye drop bottle.

[0047] (2.) Liquid dose as noted.

[0048] (3.) Standard 1 cc syringe (for liquid), 29 gauge (12.7 mm)needle manufactured by Becton Dickinson, Franklin Lakes, N.J. 07417 US.A # 8-32 nut is rigidly attached co-axial with the plunger. A 5centimeter diameter wheel is rigidly attached (co-axial) to a # 8-32screw. The wheel is marked at 30 degree increments. The markings arelocated at the OD of the wheel. The objective of the screw is todisplace the plunger. The objective of the wheel is to measure therotation of the screw. The end of the screw is milled to a conical shapehaving a diameter of 0.3 millimeters at the end. A thin sheet of steelis rigidly attached to the end of the plastic plunger. Prior toattaching, a centrally located depression is formed on the sheet ofsteel. This depression is 0.5 millimeters diameter. The objective of thedepression is to maintain the location of the screw on the plunger. Thescrew is placed on the nut. This syringe is used to inject dose (6).Calculations indicate a 27 degree rotation dispenses 1 microliter

[0049] (4.) Standard 1 cc syringe (for air). This syringe is identicalto the syringe described in No. 3 above. This syringe is used to injectbubble (7).

[0050] (5.) Holding fixture “C” for the air syringe (fixed location).

[0051] (6.) Holding fixture “D” for Prototype “P1” (moveable). Theseholding fixtures maintain the needle co-axial with the flow channel.

[0052] (7.) Magnifying glass, 90 millimeter diameter, approx 5 timespower.

[0053] (8.) Scale, 100 divisions per inch, No. 305 R, manufactured by L.S. Starrett, Athol, Mass. US.

[0054] The procedure for experiments A to D include the following steps:

[0055] (1.) For dose (6), insert needle (syringe is hand held) into theflow channel (via the outlet of the flow channel), locate the tip of theneedle near wall (3), rotate wheel, wait 12 seconds, remove needle,record delta AL (angular rotation of the wheel for liquid). NOTE: Ittakes approximately 70 seconds to eject the entire quantity of liquid.And the residual liquid remaining on the needle after each trial is 0.5microliters for delta AL between 90 degrees and 210 degrees; theresidual liquid remaining on the needle is 0.2 microliters for delta ALbetween 30 degrees and 60 degrees.

[0056] (2.) For bubble (7), (while holding fixture “D” only) insertneedle (syringe is on fixture “C” and prototype “P1” is on fixture “D”)into the flow channel (via the outlet of the flow channel), locate thetip on the needle near the center of dose (6), rotate wheel, wait approx5 seconds, air is injected into dose (6), a bubble (7) is located nearthe center of dose (6), while holding fixture “D” only: remove theneedle. Record delta AA (quantity of rotation of wheel (for air) indegrees. Note: The longitudinal axis of the needle, and the longitudinalaxis of the flow channel are horizontal for steps 1 and 2. Forapproximately 1000 trials, the location of dose (6) and bubble (7) weremeasured with the above described scale and magnifying glass.

[0057] (3.) While holding fixture “D” only: rotate fixture “D” such thatthe longitudinal axis of the flow channel is vertical. Observeconfiguration of dose (6) and bubble (7).

[0058] (4.) compress bottle walls at points “S” and “T” a total distanceof approximately 3 millimeters. This displacement occurs withinapproximately 550 milliseconds. a possible time includes approximately900 milliseconds.

[0059] (5.) observe output, and record data.

[0060] In the following experiments:

[0061] delta AL is the quantity of rotation of the wheel (for dose (6)),in degrees. delta AA is the quantity of rotation of the wheel (forbubble (7)), in degrees. And the dose is the actual quantity of liquidinjected into the flow channel.

EXPERIMENT A

[0062] Results in Table I; dose (6)=TIMOLOL 0.3%, delta AL=90 degrees,dose (6)=3 microliters, delta AA=60 degrees, bubble (7)=2 microliters,air temperature at # 1 is 27.0 C and at # 21 is 24.5 C, the averagetotal time per trial is 150 seconds (this time includes the timerequired to record data). NOTE: 4 trials were executed (prior toexperiment D) with prototype “P1” utilizing TIMOLOL 0.5%, results:

[0063] Trials 1 and 2: dose (6)=3 microliters, bubble (7)=2 microliters,bubble (7) was located at the upstream end of liquid. Trials 1 and 2dispensed a microdose/1.4 mm diameter.

[0064] Trial 3: dose (6)=4 microliters, quantity 2 bubbles (7) 1microliter each, bubbles are centrally located in the liquid. Trials 3dispensed a microdose/1.8 mm diameter.

[0065] Trial 4: dose (6)=4 microliters, quantity 3 bubbles (7), firstbubble (7)=0.5 microliters located near upstream end, second bubble(7)=1 microliter located midstream, third bubble (7)=0.5 microliterslocated near downstream end. Trial 4 dispensed a microdose/2 millimetersdiameter.

[0066] For these trials 1 to 4, there was excessive residue in the flowchannel, and this is likely undesirable, therefore no furtherexperiments were executed with 0.5% liquid.

EXPERIMENT B

[0067] Results in Table II; dose (6)=CLEAR EYES, delta AL=90 degrees,dose (6)=3 microliters, delta AA=60 degrees, bubble (7)=2 microliters,air temperature at # 1 is 27.2 C, the average total time per trial is270 seconds.

EXPERIMENT C

[0068] Results in Table III; dose (6)=CLEAR EYES, delta AL=150 degrees,dose (6)=5 microliters, delta AA=60 degrees, bubble (7)=2 microliters,air temperature at # 1 is 26.5 C and at # 26 is 27.0 C, the averagetotal time per trial is 122 seconds.

EXPERIMENT D

[0069] Results in Table IV; dose (6)=SPARKLETTS distilled drinkingwater. SPARKLETTS is a product manufactured by Danone Waters of NorthAmerica, Stamford, Conn. 06902 US, delta AL=90 degrees, dose (6)=3microliters, delta AA=60 degrees, bubble (7)=2 microliters, the airtemperature at # 1 is 27.0 C and at # 17 is 25.0 C, the average totaltime per trial is 133 seconds. NOTE: this experiment includes trials #18 to 23, with a dose (6)=4 microliters, bubble (7)=2 microliters,

[0070] Results:

[0071] 4 trials dispensed a microdose/1.2 mm dia.

[0072] 2 trials dispensed overspray only.

[0073] Additional experiments with “P1” and the above liquids andparameters dispensed microdoses having a dose (6) of 7, 8, and 9microliters. The results for these 7 to 9 microliter doses are similarto the above results. Also experiments were executed with a cylindricalflow channel, 1 millimeter ID, 2 millimeter OD, 13 millimeter length,high density polyethylene. The results with this cylindrical flowchannel (for dose (6) between 3 to 5 microliters) are similar to theabove results.

[0074] The syringe and dispenser were flushed 20 times with SPARKLETTSdistilled water, prior to experiment D.

[0075] All dimensions of the diameter of the microdose are estimatesbased on visual observation. For example, the configuration of themicrodose appears to be identical for each trial, therefore, thediameter of each microdose appears to be identical, for each trial. Theaccuracy of the liquid dose is calculated to be plus or minus 0.5microliters. The same person executed all trials.

[0076] There are variations of the above describe system, which willdispense a microdose. Several of the variations are described inexperiment A. For example, there may be two or three bubbles (7), theflow channel may be cylindrical having a 1 millimeter ID, there may bealternate collapsing velocities, alternate solutions, alternate gases,alternate mechanical methods of injecting dose (6); bubble (7). Opening(4) may have alternate diameters.

[0077] The bottle compressed by hand may be replaced by a mechanicalapparatus. For example, a syringe adapted with a spring actuated piston,including others. TABLE I (TIMOLOL 0.3%) MICRODOSE TRIAL # DIAMETER  11.3 mm  2 1.3 mm  3 1.3 mm  4 1.3 mm  5 1.3 mm  6 1.3 mm & overspray  71.3 mm  8 1.3 mm  9 overspray only 10 1.3 mm 11 overspray only 12 1.3 mm13 1.3 mm 14 1.3 mm 15 overspray only 16 overspray only 17 1.3 mm 18overspray only 19 1.3 mm 20 1.3 mm 21 1.3 mm

[0078] TABLE II (CLEAR EYES) MICRODOSE TRIAL # DIAMETER  1 1.2 mm  2 1.2mm  3 1.2 mm  4 1.2 mm  5 1.2 mm  6 1.2 mm  7 1.2 mm  8 1.2 mm  9 1.2 mm10 1.2 mm 11 1.2 mm 12 1.2 mm 13 1.2 mm 14 1.2 mm 15 1.2 mm 16 1.2 mm 171.2 mm 18 1.2 mm

[0079] TABLE III (CLEAR EYES) MICRODOSE TRIAL # DIAMETER  1 1.3 mm &overspray  2 1.3 mm  3 1.3 mm  4 1.3 mm  5 1.3 mm & overspray  6 1.3 mm& overspray  7 1.3 mm  8 1.3 mm  9 1.3 mm & overspray 10 1.3 mm 11 1.3mm 12 1.3 mm 13 1.3 mm 14 1.3 mm 15 1.3 mm 16 1.3 mm 17 1.3 mm 18 1.3 mm19 1.3 mm 20 1.3 mm 21 1.3 mm & overspray 22 1.3 mm 23 1.3 mm &overspray 24 1.3 mm 25 1.3 mm 26 1.3 mm

[0080] TABLE IV (SPARKLETTS) MICRODOSE TRIAL # DIAMETER  1 1.2 mm  2 1.2mm  3 1.2 mm  4 1.2 mm  5 1.2 mm  6 overspray only  7 1.2 mm  8 1.2 mm 9 1.2 mm 10 1.2 mm 11 overspray only 12 overspray only 13 oversprayonly 14 1.2 mm 15 overspray only 16 overspray only 17 1.2 mm

[0081] The present Specification includes three distinct inventions asfollows:

[0082] (1.) the appended claims;

[0083] (2.) A dual microliter dose consisting essentially of:

[0084] a first dose;

[0085] a second dose wherein;

[0086] said first dose is one ball of liquid;

[0087] said second dose is one ball of gas;

[0088] said first dose encloses said second dose;

[0089] (3.) A dual microliter dosage system comprising:

[0090] a flow channel having an inlet and an outlet;

[0091] a first dose disposed within said flow channel;

[0092] said first dose encloses a second dose wherein;

[0093] said first dose is one ball of liquid;

[0094] said second dose is one ball of gas.

[0095] Inherent properties of the microdose include:

[0096] (1.) exist suspended below a surface;

[0097] (2.) exist as a discrete article;

[0098] (3.) form a particular and repeatable overall size;

[0099] (4.) form one accurate and repeatable dose;

[0100] (5.) form two accurate and repeatable doses.

[0101] The present Specification includes specific doses, and thesespecific doses are presented for example only, and therefor, the rangeof the first dose, range of the second dose, particular first dose, orparticular second dose, which dispense a microdose, can be empiricallydetermined.

[0102] Obviously, many modifications and variations of the presentinvention, as hereinbefore set forth, may be made without departing fromthe spirit and scope thereof, and therefor, only such limitations shouldbe imposed as are indicated by the appended claims.

I claim:
 1. A microdose suspended below a surface comprising: a firstdose; a second dose wherein; said first dose is one ball of liquid; saidfirst dose encloses said second dose; said second dose is one ball ofgas; said first dose is suspended below a surface.
 2. The microdosesuspended below a surface according to claim 1 wherein, said first doseis between approximately 3 microliters to approximately 9 microliters;said second dose is approximately 2 microliters.
 3. The microdosesuspended below a surface according to claim 1 wherein, said first doseencloses a plurality of said second dose.